A nerve cell constitutes one unit, called a neuron, consisting of a nerve cell body, dendrites and an axon. Neurons together form a junctional area called a synapse, and transmit sensory impulses from the periphery, or signals such as motor commands from the brain. In the brain, nerve cells form synapses complicatedly and elaborately to produce higher functions, such as mental activity, memory, speech, behavior and cognition. Degeneration or death of nerve cells impairs the function of nerve cells, and may cause disorder of higher functions.
Degeneration or death of a nerve cell is generally classified as necrosis typified by ischemic necrosis, and apoptosis which is a cellular death actively caused by the cell itself. Necrosis begins with swelling of the cell and collapse of the cytoplasm, caused by energy exhaustion due to ischemia, excitation due to influx of an excitatory amino acid or voltage-gated calcium, or damage due to a free radical. Apoptosis, on the other hand, includes delayed neuronal death which is observed several days after ischemia, or that which occurs because a substance like an abnormal protein is accumulated in the cytoplasm. Apoptosis mainly involves shrinkage of the cell, condensation of cell nuclear chromatin, and fragmentation of nuclear DNA, although details of the mechanism of apoptosis are unknown.
Many cerebral diseases involve degeneration or death of nerve cells, and they are roughly divided into those due to ischemia and those not caused by ischemia.
Of the cerebral diseases due to ischemia, cerebrovascular disorders occur most frequently, and they are classified by cause into thrombotic infarction due to arteriosclerosis of a cerebral vessel, cardio-embolic infarction, hypertensive intracerebral bleeding, and subarachnoid hemorrhage following rupture of cerebral aneurysm. As a result, these cerebrovascular disorders present with varieties of neuropsychological symptoms, such as aphasia, apraxia, agnosia, emotional or memory disturbance, and dementia. Nerve cells are very vulnerable to ischemia. Thus, when cerebral circulation is disturbed, nerve cells are damaged, resulting in necrosis of nerve cells or local necrosis (infarction) of the brain. Cerebral hemorrhage also causes ischemia due to disruption of bloodstream, or destruction of the cerebral parenchyma due to hematoma, followed by edema of surrounding tissue in the brain or disturbance of microcirculation. In subarachnoid hemorrhage as well, ischemia due to cerebrovascular spasm develops. Such cerebrovascular disorders are treated by symptomatic therapies or drug therapies suitable for the causes. These therapies include lysis of thrombus, removal of edema, and lowering of an elevated blood pressure to the normal pressure.
When restoration of the bloodstream begins after ischemia, free radicals sharply increase, and leukocytes are activated to produce cytokines. Furthermore, the endothelium, thrombocytes and blood coagulation are activated to accelerate infarction. Factors inducing such degeneration and necrosis of cells include, for example, energy reduction due to ATP depletion, cell acidosis, glutamate release, calcium ion influx, membranous phospholipid degradation and subsequent free fatty acid accumulation, and free radical generation.
In view of these factors, research and development have been performed of drugs, such as calcium channel blockers, platelet aggregation inhibitors, glutamate antagonists, CDP-amines, free radical scavengers/antioxidants, perfluorocarbons, and thrombolytic agents for improving cerebral blood flow and/or neuronal output. Many such agents for treatment of diseases associated with ischemic events of the brain have been studied and developed, but satisfactory drugs are still unavailable.
Examples of cerebral diseases not ascribed to ischemia are what we call neurodegenerative diseases in which a certain line of nerve cells fall off. Representative of them are Alzheimer disease and Parkinson disease. Cholinesterase inhibitors aimed at activation of cholinergic nerves are used for treatment of Alzheimer disease. L-DOPA has long been used as a drug for treatment of Parkinson disease. However, these drugs do not suppress the death of nerve cells.
In addition to the above-described cerebral diseases, incidents, such as trauma, infection, tumor, metabolic disorder and drug intoxication, injure nerve cells. Examples of these incidents are traumatic cerebrovascular disorder, traumatic neuropathic Alzheimer disease, AIDS encephalopathy, hepatic encephalopathy, anticancer drug-induced peripheral neuropathy and diabetic neuropathy. Drugs effective for these diseases are also desired.
It is extremely difficult to repair functions, or reconstruct cerebral higher functions, which have been lost by degeneration or death of nerve cells. Thus, how to prevent degeneration or death of nerve cells is of vital importance.
There are a class of synthetic compounds called growth hormone releasing peptide(GHRP)-like compounds or growth hormone secretagogues (GH secretagogues, GHS) (Bowers C. Y. (Cell. Mol. Life Sci.(1998) 54: 1316-1329), Smith R. G. et al. (Endocr. Rev.(1997) 18: 621-645)) which secrete growth hormone (GH). The mechanism of GH secretion is unknown, but is considered to be mediated by GHRP/GHS receptors present in the hypothalamus or the pituitary. GHRP/GHS receptors also exist in the cerebral cortex or the hippocampus (Mol. Brain Res.(1997) 48: 23-29, Endocrinology (1997)138: 4552-4557). The existence of GHRP/GHS receptors of a different subclass is also reported (Circ. Res.(1999) 85: 796-802). However, little has been known about the roles in the brain of growth hormone releasing peptide-like compounds or GH secretagogues mediated by these receptors.